Hunting for Magic Bullets
Because of the increasing resistance of microorganisms to current antimicrobial medications, the demand for new antimicrobials that will kill these resistant organisms is rapidly increasing. It is surprising and sobering to realize that only two new classes of antimicrobials have been introduced in the past 40 years. The challenge is great to develop new antimicrobial agents that strike at targets different from the few used by current antimicrobials.
With the revolution that has been occurring in biology over the past 15 years, the development of new antimicrobial agents may become a reality. Promising new strategies are based on knowing the genomic sequence of microbial pathogens. Close to 100 microbial genomes have now been sequenced, many of which are human pathogens. The study and analysis of the nucleotide sequence of DNA is called genomics. The next step is to identify genes necessary for the survival of the microorganism or required to cause disease. To gain some understanding of the function of any gene, one must compare its DNA sequence with the sequence of all other genes that have been put into a database, called a genebank. If the gene that has been sequenced is similar in sequence to any other gene, then it is assumed that the two genes have similar functions. Thus, if the function of a gene that has been sequenced in any organism is known, the function of all genes with a similar sequence should be similar. This is the science of bioinformatics, which involves the analysis of the nucleotide sequence of DNA in order to understand what it codes for. Genes that are required for virulence in the pathogen but are not found in the host are potential targets. It should be possible to design a protein inhibitor of the virulence protein and thereby prevent disease.
To develop successful enzyme inhibitors requires considerable information about the enzyme, how it folds, what its three-dimensional structure is, and whether or not it interacts with other proteins.
In the past, the search for antimicrobial medications has relied on random screening. Scientists looked for growth inhibition of a pathogen by unknown organisms isolated from soil samples collected from around the world. Today, new technologies based on microbial genomics should identify new targets and provide a rational approach to developing new antimicrobials.
216 Chapter 8 Bacterial Genetics
8.1 Diversity in Bacteria
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